A vonoprazan fumarate composition and preparation method thereof

Abstract

The present invention provides a vonoprazan fumarate composition and a preparation method thereof, belonging to the field of medical technology. Specifically, a vonoprazan fumarate composition is provided, comprising the following components: vonoprazan fumarate, vitamin C, an oil phase, and sodium bicarbonate or calcium carbonate; a preparation method of the vonoprazan fumarate composition is also provided. The vonoprazan fumarate composition provided by the present invention greatly improves the efficacy of treating gastric diseases, reduces the dosage of vonoprazan fumarate, and effectively solves the problem of large toxic and side effects of existing vonoprazan fumarate agents.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a vonoprazan fumarate composition and a preparation method thereof. Background Art

[0002] Vonoprazan fumarate is a potassium-competitive acid blocker used to treat acid-related conditions, including Helicobacter pylori infection, gastroesophageal reflux, peptic ulcers, duodenal ulcers, gastric ulcers, and esophagitis. Some patients have experienced immune system disorders, including anaphylactic shock, drug-induced dermatitis, and urticaria; others have experienced hepatobiliary disorders, including hepatotoxicity and jaundice; and, in rare cases, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. To minimize side effects, every patient taking Walker's Vonoprazan fumarate tablets must strictly adhere to the prescribed dosage or take the medication as directed by a physician. The minimum dosage of single-dose Vonoprazan fumarate tablets currently available internationally is 10mg, but this still carries the aforementioned side effects. Doses below this dosage are ineffective in treating gastric acid-related conditions.

[0003] Vonoprazan fumarate tablets are already on the market. Due to patent issues, only the original developer, Takeda Pharmaceuticals of Japan, produces and sells this drug in China. Excipients used in the original developer include mannitol, fumaric acid, hydroxypropyl cellulose, croscarmellose sodium magnesium stearate, and coating powder. The tablets are compressed into tablets through wet granulation or fluidized bed granulation, and then coated with a coating solution. Mannitol serves as a filler, fumaric acid as a stabilizer, hydroxypropyl cellulose and croscarmellose sodium as disintegrants and binders, respectively, and magnesium stearate as a lubricant.

[0004] Literature research shows that the currently marketed vonoprazan fumarate preparations have the following adverse reactions and toxic side effects: Immune system diseases: drug hypersensitivity reactions (including anaphylactic shock), drug-induced dermatitis, urticaria; Hepatobiliary system diseases: hepatotoxicity, jaundice; Skin and subcutaneous tissue diseases: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis; Hepatotoxicity: Abnormal liver function (including liver damage) has been reported in clinical trials, and such reports have also been received after marketing, many of which occurred shortly after the start of treatment. Close observation should be conducted, and if there is evidence of abnormal liver function or signs or symptoms suggesting liver dysfunction, appropriate measures including drug discontinuation should be taken; Taking existing products may mask the symptoms of gastric malignancies, and the possibility of malignant tumors should be ruled out before starting this product; An observational study conducted abroad (mainly involving hospitalized patients) reported an increased risk of gastrointestinal infections caused by Clostridium difficile in patients receiving proton pump inhibitors. Pseudomembranous colitis may be caused by the combined use of antibiotics during the eradication of Helicobacter pylori. If abnormal pain or frequent diarrhea occurs, appropriate measures, including discontinuation of the drug, should be taken. Several observational studies conducted abroad reported an increased risk of osteoporosis-related hip, wrist, or spinal fractures during proton pump inhibitor treatment, and the increased risk of fractures was more significant in patients receiving high-dose or long-term (≥1 year) treatment. Vonoprazan should be used with caution in patients with kidney disease and liver disease because the metabolism and excretion of vonoprazan may be delayed, leading to increased vonoprazan concentrations in the blood. Studies have reported that benign gastric polyps have been observed during long-term administration of this product.

[0005] All of the above adverse reactions are positively correlated with the dosage. Since the marketed drug is a single-ingredient preparation, a conventional dosage of 10mg-20mg is recommended to ensure adequate therapeutic efficacy. To address the significant toxicity and side effects of existing single-ingredient vonoprazan fumarate drugs, there is currently a lack of low-dose vonoprazan fumarate-related drug products on the market with reduced side effects. Summary of the Invention

[0006] In view of the deficiencies in the prior art, the present invention provides a vonoprazan fumarate composition and a preparation method thereof.

[0007] The vonoprazan fumarate composition provided by the present invention greatly improves the efficacy of treating gastric diseases, reduces the dosage of vonoprazan fumarate, and effectively solves the problem of large toxic and side effects of existing vonoprazan fumarate agents.

[0008] The technical solutions of the present invention are as follows:

[0009] A vonoprazan fumarate composition comprises the following components: vonoprazan fumarate, vitamin C, an oil phase, and sodium bicarbonate or calcium carbonate.

[0010] According to the present invention, the oil phase is preferably one or more of sesame oil, sunflower oil, peanut oil and soybean oil.

[0011] More preferably, the oil phase is sesame oil.

[0012] According to a preferred embodiment of the present invention, the composition further comprises an emulsifier and an auxiliary emulsifier.

[0013] More preferably, the emulsifier is one or more of PEG400, PEG4000, PEG6000, and natural beeswax;

[0014] The auxiliary emulsifier is one or more of Tween 80, 1,2-propylene glycol and glycerol.

[0015] More preferably, the emulsifier is PEG4000 or PEG400; and the co-emulsifier is Tween 80.

[0016] Further preferably, the components of the composition include the following by weight: 0.7-1.8 parts of vonoprazan fumarate, 5-30 parts of vitamin C, 0.5-5 parts of sodium bicarbonate or calcium carbonate, 20-60 parts of oil phase, 5-30 parts of emulsifier, and 0.5-1.5 parts of co-emulsifier.

[0017] More preferably, the components of the composition include the following by weight: 0.5-1.5 parts of vonoprazan fumarate, 5-15 parts of vitamin C, 0.5-2.0 parts of sodium bicarbonate or calcium carbonate, 30-50 parts of oil phase, 15-30 parts of emulsifier, and 0.8-1.2 parts of co-emulsifier.

[0018] According to a preferred embodiment of the present invention, the composition is in the form of a soft capsule.

[0019] More preferably, in each capsule, the mass of vonoprazan fumarate is 5 mg, the mass of sodium bicarbonate is 5 mg, the mass of vitamin C is 50 mg, and the mass of sesame oil is 205 mg.

[0020] Further preferably, the capsule material of the capsule shell includes gelatin, water, plasticizer, pigment, and sunscreen.

[0021] More preferably, the plasticizer is glycerin and the sunscreen is titanium dioxide.

[0022] The preparation method of the vonoprazan fumarate composition comprises the following steps:

[0023] (1) Dissolve purified water, vonoprazan fumarate, and vitamin C in appropriate parts by weight, add an emulsifier, heat to 60-80° C., and mix well to prepare an aqueous phase;

[0024] (2) Sodium bicarbonate or calcium carbonate, an emulsifier, and sesame oil are heated to 60-80° C. according to corresponding weight parts, and mixed uniformly to obtain a mixture. The mixture is added to the aqueous phase obtained in step (1), and stirred to obtain a microemulsion.

[0025] Preferably according to the present invention, in step (1), the weight portion of pure water is 20 parts.

[0026] According to a preferred embodiment of the present invention, in step (2), the prepared microemulsion is prepared into a soft capsule dosage form.

[0027] Further preferably, the capsule material of the capsule shell includes gelatin, water, plasticizer, pigment, and sunscreen.

[0028] More preferably, the plasticizer is glycerin and the sunscreen is titanium dioxide.

[0029] Beneficial effects

[0030] The vonoprazan fumarate composition provided by the present invention greatly improves the efficacy of treating gastric diseases, reduces the dosage of vonoprazan fumarate, and effectively solves the problem of large toxic and side effects of existing vonoprazan fumarate agents. DETAILED DESCRIPTION

[0031] The present invention is further described in detail below with reference to the embodiments, but the protection scope of the present invention is not limited thereto.

[0032] Unless otherwise specified, the reagents and raw materials involved in the examples are common commercially available products; the operating steps and methods involved in the examples are routine operations in the art unless otherwise specified.

[0033] Example 1

[0034] A soft capsule dosage form of a vonoprazan fumarate composition, the components and proportions of which are shown in Table 1:

[0035] Each tablet of vonoprazan fumarate contains 5 mg.

[0036] Table 1

[0037]

[0038]

[0039] The preparation method of the vonoprazan fumarate composition capsule dosage form comprises the following steps:

[0040] (1) Weigh purified water, vonoprazan fumarate, and vitamin C by weight, mix and stir to dissolve, then add PEG4000 and PEG400, heat to 70°C, and stir to mix evenly to prepare an aqueous phase;

[0041] (2) Weigh sodium bicarbonate, Tween 80, and sesame oil by weight, heat to 70° C., mix well, and add them one by one to the aqueous phase prepared in step (1), while stirring at 60 rpm for 2 hours to avoid forming lumps, and obtain a microemulsion with uniform texture and no obvious graininess;

[0042] (3) Gelatinization: Add purified water by weight into a gelatinization tank, slowly heat to 65°C, add glycerin, stir evenly, heat to 85°C, add titanium dioxide and red iron oxide, stir evenly, add gelatin, stir for 1.5 hours, remove bubbles, and keep warm (55°C) for later use;

[0043] (4) Pellet pressing: Adjust the temperature of the preparation room to 20±5°C and the humidity to 40±5%; set the temperature of the sol tank to 75°C, the temperature of the glue box to 55°C, and the temperature of the spray body to 40±5°C; adjust the thickness of the rubber to be maintained at 0.8±0.2mm, and automatically fill the microemulsion prepared in step (2) and press it into pellets;

[0044] (5) Shaping: Shaping the soft capsules pressed into pellets in step (4) at a temperature of 25 ± 5 °C for 1.5 h;

[0045] (6) Pill washing: After setting, pour out the soft capsules and wash them to remove the emulsifier on the surface of the soft capsules and the contents after compression and crushing (i.e., microemulsion). Use anhydrous ethanol for rapid washing and then dry.

[0046] (7) Drying: The washed soft capsules are spread flat on a drying rack to prevent adhesion and breakage. The temperature in the drying room is maintained at 25±5°C and the humidity is maintained at 35±5%. Dry for 36 hours to obtain the soft capsules of the present invention.

[0047] Example 2

[0048] A soft capsule dosage form of a vonoprazan fumarate composition, the components and proportions of which are shown in Table 2:

[0049] The specification of vonoprazan fumarate is 5mg.

[0050] Table 2

[0051]

[0052]

[0053] The preparation method of the vonoprazan fumarate composition soft capsule dosage form comprises the following steps:

[0054] (1) Weigh purified water, vonoprazan fumarate, and vitamin C by weight, mix and stir to dissolve, then add PEG4000 and PEG400, heat to 70°C, and stir to mix evenly to prepare an aqueous phase;

[0055] (2) Weigh sodium bicarbonate, Tween 80, and sesame oil by weight, heat to 70° C., mix well, and add them one by one to the aqueous phase prepared in step (1), while stirring at 60 rpm for 2 hours to avoid forming lumps, and obtain a microemulsion with uniform texture and no obvious graininess;

[0056] Steps (3) to (7) are the same as in Example 1.

[0057] Example 3

[0058] A soft capsule dosage form of a vonoprazan fumarate composition, the components and proportions of which are shown in Table 3:

[0059] The specification of vonoprazan fumarate is 5mg.

[0060] Table 3

[0061]

[0062]

[0063] The preparation method of the vonoprazan fumarate composition soft capsule dosage form comprises the following steps:

[0064] (1) Weigh purified water, vonoprazan fumarate, and vitamin C by weight, mix and stir to dissolve, then add PEG4000 and PEG400, heat to 70°C, and stir to mix evenly to prepare an aqueous phase;

[0065] (2) Weigh calcium carbonate, Tween 80, and sesame oil by weight, heat to 70° C., mix well, and add them one by one to the aqueous phase prepared in step (1), while stirring at 60 rpm for 2 hours to avoid forming lumps, and obtain a microemulsion with uniform texture and no obvious graininess;

[0066] Steps (3) to (7) are the same as in Example 1.

[0067] Example 4

[0068] A soft capsule dosage form of a vonoprazan fumarate composition, the components and proportions of which are shown in Table 4:

[0069] The specification of vonoprazan fumarate is 5mg.

[0070] Table 4

[0071]

[0072]

[0073] The preparation method of the vonoprazan fumarate composition soft capsule dosage form comprises the following steps:

[0074] (1) Weigh purified water, vonoprazan fumarate, and vitamin C by weight, mix and stir to dissolve, then add PEG4000 and PEG400, heat to 70°C, and stir to mix evenly to prepare an aqueous phase;

[0075] (2) Weigh sodium bicarbonate, Tween 80, and sesame oil by weight, heat to 70° C., mix well, and add them one by one to the aqueous phase prepared in step (1), while stirring at 60 rpm for 2 hours to avoid forming lumps, and obtain a microemulsion with uniform texture and no obvious graininess;

[0076] Steps (3) to (7) are the same as in Example 1.

[0077] Example 5

[0078] A soft capsule dosage form of a vonoprazan fumarate composition, the components and proportions of which are shown in Table 5:

[0079] The specification of vonoprazan fumarate is 5mg.

[0080] Table 5

[0081]

[0082]

[0083] The preparation method of the vonoprazan fumarate composition soft capsule dosage form comprises the following steps:

[0084] (1) Weigh purified water, vonoprazan fumarate, and vitamin C by weight, mix and stir to dissolve, then add PEG4000 and PEG400, heat to 70°C, and stir to mix evenly to prepare an aqueous phase;

[0085] (2) Weigh calcium carbonate, Tween 80, and sesame oil by weight, heat to 70° C., mix well, and add them one by one to the aqueous phase prepared in step (1), while stirring at 60 rpm for 2 hours to avoid forming lumps, and obtain a microemulsion with uniform texture and no obvious graininess;

[0086] Steps (3) to (7) are the same as in Example 1.

[0087] Example 6

[0088] The difference from Example 1 is that sunflower seed oil is used instead of sesame oil, and all other aspects are the same.

[0089] Example 7

[0090] The difference from Example 1 is that peanut oil is used instead of sesame oil, and everything else is the same.

[0091] Example 8

[0092] The difference from Example 1 is that soybean oil is used instead of sesame oil, and all other aspects are the same.

[0093] Comparative Example 1

[0094] The difference from Example 1 is that the amount of vonoprazan fumarate in the composition is 10 mg, and the other aspects are the same.

[0095] Comparative Example 2

[0096] The difference from Example 1 is that vonoprazan fumarate is not added, and the other aspects are the same.

[0097] Comparative Example 3

[0098] The difference from Example 1 is that vitamin C is not added, and all other aspects are the same.

[0099] Comparative Example 4

[0100] The difference from Example 1 is that sesame oil is not added, and all other aspects are the same.

[0101] Comparative Example 5

[0102] The difference from Example 1 is that vitamin C and sesame oil are not added, and everything else is the same.

[0103] Effect Examples

[0104] The adverse reactions after taking the soft capsules prepared in Examples 1-8, the soft capsules prepared in Comparative Examples 1-5 and the original reference preparation were compared, as shown in Tables 6 to 44.

[0105] The dosage of the soft capsules prepared in Examples 1-8 of the present invention and the soft capsules prepared in Comparative Examples 1-5 is once a day, one capsule each time.

[0106] The original reference preparation is produced by Tianjin Takeda Pharmaceutical Co., Ltd. and consists of vonoprazan fumarate, mannitol, microcrystalline cellulose, hydroxypropyl cellulose, magnesium stearate, fumaric acid, etc. Take once daily, one tablet each time, each tablet is 20 mg.

[0107] Table 6

[0108]

[0109] Table 7

[0110]

[0111] Table 8

[0112]

[0113] Table 9

[0114]

[0115] Table 10

[0116]

[0117] Table 11

[0118]

[0119] Table 12

[0120]

[0121] Table 13

[0122]

[0123] Table 14

[0124]

[0125] Table 15

[0126]

[0127] Table 16

[0128]

[0129] Table 17

[0130]

[0131] Table 18

[0132]

[0133] Table 19

[0134]

[0135] Table 20

[0136]

[0137] Table 21

[0138]

[0139] Table 22

[0140]

[0141] Table 23

[0142]

[0143] Table 24

[0144]

[0145] Table 25

[0146]

[0147] Table 26

[0148]

[0149] Table 27

[0150]

[0151] Table 28

[0152]

[0153] Table 29

[0154]

[0155] Table 30

[0156]

[0157] Table 31

[0158]

[0159] Table 32

[0160]

[0161] Table 33

[0162]

[0163] Table 34

[0164]

[0165]

[0166] Table 35

[0167]

[0168] Table 36

[0169]

[0170] Table 37

[0171]

[0172] Table 38

[0173]

[0174] Table 39

[0175]

[0176]

[0177] Table 40

[0178]

[0179] Table 41

[0180]

[0181] Table 42

[0182]

[0183] Table 43

[0184]

[0185] Table 44

[0186]

[0187]

[0188] According to the above experimental data, it can be seen from the effect data of the compositions provided in Examples 1-8 that the compositions provided by the present invention improve the efficacy of treating gastric diseases and reduce adverse reactions, especially the compositions provided in Examples 1-5 have better effects.

[0189] In Comparative Example 1, the amount of vonoprazan fumarate was doubled, and its adverse reactions were found to increase, but the cure rate did not change much. This shows that increasing the amount of vonoprazan fumarate in the composition did not significantly improve the therapeutic effect, but instead increased the number of adverse reactions. In Comparative Example 2, vonoprazan fumarate was not added, and its therapeutic effect was found to be poor, indicating that the composition cannot achieve a therapeutic effect without vonoprazan fumarate and can only work when combined. In Comparative Example 3, vitamin C was not added. The therapeutic effect was close to that of the reference, and the adverse reactions were also basically the same, but it was slightly higher than the adverse reactions in the examples, indicating that vitamin C has a certain effect in reducing adverse reactions. In Comparative Example 4, sesame oil was not added. The therapeutic effect was close to that of the reference, and the adverse reactions were also basically the same, but it was slightly higher than the adverse reactions in the examples, indicating that sesame oil also has a certain effect in reducing adverse reactions. In Comparative Example 5, neither vitamin C nor sesame oil was added. The adverse reactions were relatively more than those in the example test group, indicating that if neither vitamin C nor sesame oil is added, the effect of reducing adverse reactions will be significantly reduced.

[0190] Based on the above results, it can be seen that the composition provided by the present invention improves the efficacy of treating gastric diseases and reduces adverse reactions; in particular, the combination of vitamin C, sesame oil and vonoprazan fumarate in the composition of the present invention has a significant effect in improving the efficacy and reducing adverse reactions, thereby proving that the present invention has significant innovation in increasing the efficacy and reducing adverse reactions.

Claims

1. A vonoprazan fumarate composition, characterized in that The components of the composition include the following by weight: 0.7-1.8 parts of vonoprazan fumarate, 5-15 parts of vitamin C, 0.5-2.0 parts of sodium bicarbonate or calcium carbonate, 30-50 parts of oil phase, 15-30 parts of emulsifier, and 0.8-1.2 parts of co-emulsifier; The oil phase is one or more of sesame oil, sunflower oil, peanut oil and soybean oil; The emulsifier is one or both of PEG4000 and PEG400; The co-emulsifier is Tween 80; The dosage form of the composition is soft capsule.

2. The composition according to claim 1, wherein The capsule material comprises gelatin, water, plasticizer, pigment and sunscreen.

3. The composition according to claim 2, wherein The plasticizer is glycerin and the sunscreen is titanium dioxide.

4. The composition according to claim 1, wherein Each capsule contains 5 mg of vonoprazan fumarate, 5 mg of sodium bicarbonate, 50 mg of vitamin C, and 205 mg of sesame oil.

5. The method for preparing the vonoprazan fumarate composition according to any one of claims 1 to 4, characterized in that: The steps include: (1) Dissolve purified water, vonoprazan fumarate, and vitamin C in appropriate parts by weight, add an emulsifier, heat to 60-80°C, and mix well to prepare an aqueous phase; (2) Sodium bicarbonate or calcium carbonate and an emulsifier are heated to 60-80° C. according to corresponding weight parts, and mixed evenly to obtain a mixture. The mixture is added to the aqueous phase obtained in step (1) and stirred to obtain a microemulsion; the microemulsion is prepared into a soft capsule dosage form.

6. The preparation method according to claim 5, wherein In step (1), the weight portion of pure water is 20 parts.

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